A variety of DNA and RNA viruses cause autoimmune responses in humans and autoimmune disease in experimental models. This grant is concerned with dissecting and understanding the molecular mechanism(s) whereby multiple and sequential virus infections break immunologic unresponsiveness to "self" antigens and cause autoimmune manifestations and disease. We developed two models where a viral protein (virus A) is expressed in beta cells of the islets of Langerhans or in oligodendrocytes using cell-specific promoters. In both, disease does not occur unless the host is challenged with virus A (disease incidence >90%, beta cell destruction by T cells resulting in hyperglycemia and hypoinsulinemia or T cell infiltration from the periphery into the CNS [white matter] and focal myelin loss). When a different virus B or C are used for the initial challenge disease does not occur but when viruses B or C are given four to six weeks after the initial inoculation with virus A, the kinetics and severity of disease is enhanced. The first business of this grant is to determine the mechanism by which multiple related or unrelated viral infections can enhance autoimmune disease. We will determine, by the use of the well established RIP-LCMV model of virus-induced autoimmune diabetes, whether the cross-reactive immune response is specific (shared peptide T cell epitopes) or due to bystander (cytokines, adhesion molecules) effects. Further, responses to self antigens (peptides) might contribute to activation and maintenance of autoreative T-lymphocytes. "Self" antigens that contain the same MHC motif as the transgene's CTL epitope and bind at high affinity to the MHC allele have been uncovered. The ability of these "self" peptides to be recognized by anti-viral T cells, maintain antiviral T cell memory and participate in autoimmune disease will be evaluated. Immunopathologic changes occur in normal islets transplanted under the renal capsule of transgenic mice developing IDDM. The second order of business is to determine the role of "self" (islet-cell) antigens other than the initial triggering viral antigen in the pathogenetic process leading to and determine their role in IDDM.